Malaria is the most prevalent among the insect borne disease accounting for more than two million deaths out of 400 million cases reported each year (Greenwood et. al., Nature 9415), 670(2002)) caused by Plasmodium falciparum. (Depote et al. Trends in parasitology (20), 4, 165-198, (2004)). More than half of the world's population lives in areas where they remain at risk of malarial infection (Sachs et at Nature, (415), 686 (2002). The derivation of important anti-malarial compound started with the discovery of cinchona bark powder (quinine) (Brooking, G B 106430, (1917)) in 1820. Subsequently post World War-I was a period of intense work in maintaining such ethnobotanical records in which the use of quinine has remained the drug of choice of malaria. In 1940 another anti-malarial drug chloroquine (Ringwald et al, Bulletin of the world health organization, 77(1), 34, (1999)) was synthesized and until recently this was the only drug used for the treatment of malaria. Unfortunately, after an early success, the malarial parasite especially P. falciparum became resistant to chloroquine. Treatment of chloroquine resistant malaria (White et al. Delaying anti-malarial drug resistance with combination chemotherapy Parasitologia, (41), 301-308, (1999)) was done with alternative drug or drug combination (Tulp et. al, Drug discovery today (9)450, (2004)) which are rather expensive and sometimes toxic. Furthermore, these combinations are not always dependent upon pharmacokinetic principle due to inadequate knowledge of metabolism and mechanism of action of most anti-malarial drugs. In the last few years a plant based anti-malarial drug isolated from the Chinese plant Artimisinin annua (Klayman, Science (228), 1049, (1985)), Bharel et al. Fitoterapia, (67), 387-399, (1996)) proved to be very active against P. falciparum. However, the use of Artemisinin, an endoperoxide sesquiterpene lactone is somewhat limited because of its relatively high cost, limited production of GMP standards and reports of toxicity (Haynes et al. Curr. Opin. Infect. Dis, (14), 719-726, (2001)). The current route for the total synthesis of Artemisinin (Qinghaosu) (U.S. Pat. No. 6,710,074 (2004) is too complex for commercial production (Schmid et al J. Am. Chem. Soc. (105), 624-625, (1983). It is currently prepared by large scale extraction from Artemisia annua (sweet warwood) and derivative such as artemether, artesunate, arteether and dihydroartemisinin are prepared semi synthetically from the purified extract. Moreover, difficulties have also been encountered in the production of high quality material (Haynes et al. Curr. Opin. Infect. Dis., (14), 719-726, (2001)).
Thus, the widespread resistance of malarial parasite to the majority of drugs, necessitates the development of new drug (Wiesner et al. Angew. Chem. Int: Ed. (42), 5274-5293, (2003)) which should be structurally different from classical compounds with novel mechanism of action to overcome the resistance problem. Recently Ihara et. al disclosed about compounds having anti-malarial activity (U.S. Pat. No. 6,710,074 (2002)) from synthesis. In recent past different classes of compound are also reported having anti-malarial activity like substituted 1,2,4 trioxane (U.S. Pat. No. 6,737,438 (2002)), flavonoids (WO2004000306 (2003)), naphthylisoquinoline (U.S. Pat. No. 6,627,641 (2003)), indoloquinazoles (U.S. Pat. No. 6,531,487 (2003)), trioxolanes (U.S. Pat. No. 6,486,199 (2002)), betacarboline alkaloids (U.S. Pat. No. 6,143,756 (2000)), vocamine (WO 9948501(1999)), acetyl glucosamine derivatives. (DE3220426(1983)) and so on. Recently many patents like U.S. Pat. No. 6,710,074, WO2004000319, U.S. Pat. No. 5,264,726, US2003212098, WO2004000306, EP1076057, WO9948501, U.S. Pat. No. 5,290,553, U.S. Pat. No. 6,143,756 and U.S. Pat. No. 6,627,641 disclosed compounds having anti Plasmodium falciparum activity from natural origin mainly plants. Hence the ethnopharmacologial approach for the search of new anti-malarial has proved to be more predictive.
As a part of ongoing research programmes on bioresources, we have screened large number of plants from the north eastern region for the anti-malarial inhibition studies. Plant selection was mainly based on various criteria such as chemotaxonomic data, field observation and random collection.
Malaria is caused by protozoa of the genus Plasmodium. Because of its prevalence, virulence and drug resistance, it is the most serious and widespread parasitic disease encountered by mankind. The inadequate armory of drugs in widespread use for the treatment of malaria and lack of affordable new drugs are the limiting factors in the fight against malaria, which underscores the continuing need of research for development of new drugs.
There is therefore a need to develop new active compounds as an alternative to chloroquine and especially from artemisinin, a plant based anti-malarial drug isolated from the Chinese plant Artemisia annua. The urgent need is to investigate the natural source with new ethanophramacological approach for the search of new anti-malarial especially from the North Eastern part of India, which has not been screened so far. Another need is to develop suitable method for the extraction, isolation and identification of bioactive principles form the plant extract having the anti-malarial properties. The recently developed new isolation and characterization techniques together with development of new pharmacological testing have led to interest in plants as a source of new drugs. However, a promising approach is needed to use these agents as templates for designing new derivatives with improve properties.